Down-regulation of MHC class l molecules by HCMV US2

HCMV US2 下调 MHC I 类分子

• 批准号: 7039054
• 负责人: Domenico Tortorella
• 金额: $ 33.1万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039054
• 关键词: MHC class I antigen; RNA binding protein; antigen presentation; clinical research; cytomegalovirus; cytotoxic T lymphocyte; gene targeting; histocompatibility gene; immune response genes; immune system; immunogenetics; immunoregulation; virus genetics; virus infection mechanism; virus protein

DESCRIPTION (provided by the applicant): Human cytomegalovirus (HCMV) is a beta-herpes virus that can establish persistence and latent infections. HCMV can cause morbidity and mortality in immuno-compromised individuals such as transplant-recipients and HIV-infected persons. In fact, HIV-positive patients are at risk of HCMV-related blindness. HCMV is also a major infectious cause of birth defects in newborns causing hearing disturbances and mild forms of mental retardation. Selective pressure by the immune system on viruses has resulted in their ability to generate evasive tactics to avoid immune detection. HCMV expresses proteins that modulate both the innate and adaptive branches of the immune system. Cellular immunity appears to be the main target of HCMV with an emphasis on interfering with CD8+ cytotoxic T cell (CTL) activation. HCMV encoded gene products from the unique short region of the genome US2, US3, US6 and US11 interfere with CTL recognition of HCMV-infected cells by preventing the surface expression of major histocompatibility complex (MHC) class I molecules. This strategy would limit the frequency of CTLs directed against HCMV epitopes during the early phase of HCMV infection and allow HCMV to escape immune detection. US2 and US11 target class I molecules for proteasomal degradation. Recent evidence suggests that US2 may also target the MHC class II DRalpha and DMalpha molecules for proteasomal degradation. This suggests that US2 is an important gene in the HCMV repertoire of viral proteins that modulates the immune system. To that end, we will define the specific regions of US2 responsible for targeting MHC class I molecules for destruction as well as identify the cellular proteins that facilitates the degradation process. We will mimic the early phase of HCMV infection and determine the function of US2 in the context of other viral gene products such as US3 and US11. A full understanding of how HCMV US2 manipulates the cellular machinery of the host to prevent MHC class I and class II antigen presentation may permit the design of pharmaceutical agents that block US2 function.

描述（由申请人提供）：人类巨细胞病毒（HCMV）是一种乙型疱疹病毒，可以建立持续性和潜伏性感染。HCMV可在免疫功能受损的个体（如移植受体和hiv感染者）中引起发病和死亡。事实上，hiv阳性患者有hcmv相关失明的风险。丙型巨细胞病毒也是新生儿出生缺陷的主要传染原因，可导致听力障碍和轻度智力迟钝。免疫系统对病毒的选择性压力导致它们产生逃避策略以避免免疫检测的能力。HCMV表达调节免疫系统先天和适应性分支的蛋白质。细胞免疫似乎是HCMV的主要目标，其重点是干扰CD8+细胞毒性T细胞（CTL）的激活。HCMV编码的基因产物来自基因组独特的短区域US2、US3、US6和US11，通过阻止主要组织相容性复合体（MHC） I类分子的表面表达来干扰HCMV感染细胞的CTL识别。这一策略将限制在HCMV感染的早期阶段针对HCMV表位的ctl的频率，并允许HCMV逃避免疫检测。US2和US11针对I类分子进行蛋白酶体降解。最近的证据表明，US2也可能针对MHC II类dr α和DMalpha分子进行蛋白酶体降解。这表明US2是调节免疫系统的HCMV病毒蛋白库中的一个重要基因。为此，我们将定义US2负责靶向MHC I类分子进行破坏的特定区域，并识别促进降解过程的细胞蛋白。我们将模拟HCMV感染的早期阶段，并确定US2在其他病毒基因产物（如US3和US11）的背景下的功能。充分了解HCMV US2如何操纵宿主细胞机制以阻止MHC I类和II类抗原呈递，可能允许设计阻断US2功能的药物。